Approach
Diagnosis of VEEV infection is based on clinical suspicion, history, and physical examination, with laboratory testing to confirm diagnosis. The clinical spectrum of disease overlaps with that caused by other viral infections. As a consequence, the differential diagnosis is broad and includes herpes encephalitis, dengue, Zika, and chikungunya virus infection.
A high index of suspicion is necessary to diagnose VEEV infection since cases tend to be sporadic. Although VEEV infections are generally confined to endemic regions (i.e., Central and South America), there have been numerous reports of infection in regions where VEEV is not traditionally endemic, which has led to delays in the diagnosis.
The diagnosis of VEEV infection is suggested by the presence of clinical features (e.g., acute onset of fever, headache, myalgia, mental status changes, and gastrointestinal [GI] bleeding) in conjunction with epidemiological criteria (e.g., recent history of travelling, working, or residing in endemic regions, particularly tropical and rural regions where risk of exposure to mosquitoes is high). Other epidemiological and environmental factors that should raise suspicion include peak mosquito season, a recent period of high rainfall, or a concurrent epizootic outbreak in horses. Confirmation of the diagnosis requires laboratory investigations, consisting of serology or detection of the virus by reverse transcription-polymerase chain reaction (RT-PCR) or viral isolation.
History
Patients usually report a history of exposure to mosquitoes and have lived or worked in or near tropical forests in Central or South America. Patients may also be aware of horses becoming unwell in areas close to where they were exposed to mosquitoes. If exposure occurs during an epizootic outbreak (i.e., involving infected horses), then neurological disease (e.g., encephalitis) should be considered as neurological involvement appears to be more prevalent among epizootic subtypes of VEEV (IAB and IC).[4] However, in rural areas where enzootic strains predominate (i.e., between rodents and the mosquito species Culex [Melanoconion]), neurological disease is less common; therefore, acute febrile illness should be considered.
The incubation period of VEEV in humans ranges between 1 and 10 days.[1][11] Following the incubation period, patients usually present with symptoms that resemble influenza or dengue fever, such as acute onset of fever, headache, chills, malaise, and myalgia, which lasts around 3 to 4 days.[5][11][27][32] Nausea, vomiting, diarrhoea, and arthralgia commonly accompany these symptoms. Symptoms less commonly reported include rhinorrhoea, cough, sore throat, sneezing, rash, and neurological symptoms (e.g., neck stiffness/nuchal rigidity, lethargy, drowsiness, confusion, seizures, paraesthesias, ataxia, hemiparesis).[4][5] The onset of neurological symptoms usually occurs several days into the course of illness. Presentation with an intense headache or a mild headache that progresses to a severe headache, with neck stiffness/nuchal rigidity, is suggestive of neurological involvement. However, some patients may be asymptomatic or present with very mild symptoms. Investigations in endemic areas have revealed very high VEEV seroprevalence (up to 80% of a population), in the absence of overt morbidity, indicating that there is likely a high rate of asymptomatic infection with VEEV.[26]
Central nervous system (CNS) involvement, particularly encephalitis, is a serious consequence of VEEV infection. Although absent in the majority of patients, it does appear to be more prevalent among children (up to 36% of symptomatic children).[9][11][14] Initially, patients with CNS involvement develop neck stiffness, seizures, and confusion, which can progress to somnolence and coma within days.[3][9] In such patients, mortality is high (up to 10%).[9] Neurological involvement may be milder, presenting with confusion, drowsiness, gait abnormalities, and/or hallucinations.[11] While most patients recover fully within a week, long-term sequelae include fatigue, headache, weakness, and myalgia. Diplopia, cranial nerve paresis, and personality changes may also persist.[11] Gastrointestinal bleeding has been reported in severe cases of encephalitis resulting from VEEV infection.
Physical examination
During the early stages of illness, the physical examination may reveal pyrexia, retro-orbital pain, tachypnoea, and tachycardia. These findings are also common for other arboviral infections.[3][33] Altered mental status, cranial nerve deficits, ataxia, and seizures may develop in those with severe CNS involvement. Fundoscopic examination may reveal papilloedema. Haemorrhage and/or bleeding diathesis may result in the presence of palor, petechiae, haematemesis, melaena, haematuria, and epistaxis.[4] Patients may also present with GI complications (e.g., jaundice, GI bleeding, right upper quadrant pain, and ascites) during physical examination.
In a large outbreak in Venezuela in 1995, 92.3% of 313 patients hospitalised with Venezuelan equine encephalitis (VEE) presented with fever, 90.7% with altered mental status, 70.6% with seizures, 55.9% with headache, and 54.6% with vomiting.[27] Among those hospitalised with VEE, 75.7% were under the age of 15 years.
Initial investigations
Laboratory tests should be ordered in patients presenting with signs and symptoms suggestive of VEEV infection. The specific tests ordered will depend on which tests are available in the local area, and whether neurological symptoms or signs of bleeding are present. If available, a rapid malaria antigen test or malaria smear could be carried out to rule out malaria.
A specific diagnosis can be made in acute serum samples by detection of VEEV using RT-PCR or viral isolation in Vero cells. However, sensitivities with RT-PCR and viral isolation may be low if performed in patients who are not viraemic; therefore, these tests should be done in the first three days after onset of illness when viraemia is detectable. Serologies may be performed in paired acute and convalescent sera (e.g., using an enzyme-linked immunosorbent assay [ELISA]). Both immunoglobulin M (IgM) and immunoglobulin G (IgG) become positive approximately five days after onset of illness. IgM remains positive for at least one month after onset of illness, whereas IgG likely remains positive for decades. However, ELISA (especially IgG ELISA) has low specificity for VEEV as it tends to cross-react with other alphaviruses (e.g., eastern equine encephalitis, Mayaro, and chikungunya viruses); therefore, if ELISA is used for serology, further confirmation by plaque reduction neutralisation test is warranted.
There are ongoing studies to develop real-time RT-PCR assays for VEEV complex, Madariaga virus, and eastern equine encephalitis virus using whole-genome sequences.[34] Such methods may not only speed up diagnosis, but also demonstrate increased sensitivity.
If CNS involvement is suspected, a lumbar puncture should be performed and analysed for cell count, standard chemistries (e.g., glucose, protein), culture, and viral detection by RT-PCR or viral isolation. Cell count may show pleocytosis with lymphocytic predominance. Glucose in VEEV is moderately depressed, whereas protein may be elevated.
Some of these diagnostic tests are only available in central laboratories in some endemic countries and in some government disease surveillance entities (e.g., the CDC in the US, which can perform testing upon request). In resource-poor regions, confirmatory laboratory tests are usually not available; thus, basic laboratory tests can be ordered (e.g., FBC including haematocrit, and LFTs). An FBC may reveal leukopenia (lymphopenia in particular) or leukocytosis (less predominant than leukopenia), anaemia, and/or thrombocytopenia. Frequent monitoring of haemoglobin or haematocrit is warranted if any bleeding is present. LFTs should be performed if there are any signs of hepatitis or liver failure (e.g., right upper quadrant tenderness, jaundice, ascites, or hepatomegaly).
Other investigations
CNS imaging is recommended if any neurological symptoms are present. Head CT or brain MRI may show cerebritis, oedema, or haemorrhage.[35] MRI is a better diagnostic modality than CT for the detection of encephalitis due to its ability to discern early signs of oedema and infection, but its availability, especially in endemic regions, is limited. An EEG can be done to identify non-convulsive seizure activity in patients with VEEV infection.
Chest imaging is not necessary for the diagnosis of VEEV infection; however, if neurological symptoms are present, a CXR may reveal infiltrates suggestive of interstitial pneumonia.[35]
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